Project Summary/Abstract According to the BRAIN 2025 working group report, there is a need to drastically improve the spatiotemporal resolution of positron emission tomography (PET), in order to facilitate the translation of new tracers that target neuroreceptor function and dynamic PET imaging on the milliseconds timescale. To address this challenge, we propose to demonstrate feasibility of a next generation annihilation photon detector module that, if successful, will serve as the fundamental building block of an advanced brain-dedicated PET system to be developed in follow-on work after this feasibility stage. This next-generation system design shows promise to transform the capabilities of PET in human neuroimaging through substantial (>10-fold) boosts in reconstructed image signal-to-noise ratio (SNR) and contrast-to-noise ration (CNR). Besides employing a smaller system diameter (e.g. 32 cm diameter) compared to the standard whole body PET system, this proposed enhancement is enabled by two unique features proposed (1) 100 picosecond (ps) coincidence time resolution (CTR), and (2) the ability to measure the energy and three-dimensional (3D) position of one or more annihilation photon interactions in the detector. These two new capabilities are achieved through a highly innovative scintillation detector configuration described in detail in the proposal. By precisely measuring the flight time of annihilation photons from their emission point within the patient to the detectors, the time-of-flight (TOF) PET technique enables a significant image SNR and CNR boost because it allows more events to be placed closer to their true point of emission along detector response lines of the system during the image reconstruction process. The key to better TOF-PET performance is to improve the annihilation photon pair CTR measured between any two detection elements in the system. Current commercially available PET systems achieve a CTR of roughly 350 to 800 ps full-width-at-half-maximum (FWHM). The proposed goal of 100 ps FWHM CTR alone represents a significant PET technology advance. But the novel detector configuration proposed also enables another capability not possible with the conventional PET detector. Owing to the fact that most incoming 511 keV photons undergo inter-crystal Compton scatter in the detectors, we can exploit the kinematics of that process to estimate the photon angle-of-incidence. If successful, that capability enables us to accurately position the first interaction of such multi-crystal events, but also offers the possibility to retain a high fraction of photon events that are normally rejected by a conventional PET system, such as single (unpaired) photons, random coincidences, tissue-scatter coincidences, and multiple (>2) photon coincidences. Since these normally-discarded events are over 10-fold more probable than true coincidence events in a standard PET study, this 3D position sensitive detector technology shows promise as another method to greatly boost photon sensitivity, and thus reconstructed image SNR. In this project we will design and develop two next-generation PET detectors and integrate them into MRI-compatible detector modules. The performance of these modules will be characterized outside and inside a 3 Tesla clinical MRI system to demonstrate feasibility of this concept.